Various enteric coatings have been used previously to orally administer drugs that are labile in the stomach and/or are targeted at the large intestine. See Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th Edition (1985), p. 1637.
Several prior patents describe dosage forms for selectively delivering 5-aminosalicylic acid (5-ASA) to the colon. Halskov (U.S. Pat. No. 4,496,553) describes formulations of 5-ASA with conventional enteric carriers (composed of lactose, potato starch, magnesium stearate and cellulose) that are not readily soluble at low pHs. Similarly, Canadian Patent 1,172,570 describes solid dosage forms of 5-ASA that are coated with methacrylic acid-methacrylic acid ester copolymers that are relatively insoluble in gastric fluid but highly soluble at the higher pHs found in the intestinal fluids. Other patents, such as U.S. Pat. Nos. 4,190,176 and 4,489,197, describe conjugating 5-ASA to nonabsorbable aromatic polymers via azobonds that are stable in the stomach but are cleaved enzymatically in the large intestine to release the 5-ASA.
U.S. Pat. No. 4,663,308--which is perhaps the closest art to the present invention--employs high molecular weight polymers of one or more ethylenically unsaturated monomers copolymerized with a divinylazobenzene compound to coat or otherwise entrap drugs that are labile in the stomach, have an undesirable effect in the stomach, or are targeted at the colon. Release of drug occurs via the cleavage of the azobonds by the azoreductases that abound in the colon but are not prevalent in the stomach or small intestine. The patent suggests various acrylic acid esters and amides as well as unsaturated acids as possible monomers. However, the only copolymer exemplified in the patent is a hydroxyethyl-methacrylate (HEMA)-styrene copolymer that contains no ionizable group. Further, the only ionizable group-containing polymer exemplified in the patent is a crosslinked polyacrylic acid. In this regard, drug release from the formulations of the present invention is controlled by a combination of pH-dependent swelling of the copolymer and degradation of the hydrogel via cleavage of the azobonds by the azoreductases in the colon. Further, the copolymers of U.S. Pat. No. 4,663,308 are crosslinked under the gel point (branched) and are thus soluble in organic solvents. In contrast, the copolymers of the present invention are crosslinked beyond the gel point and are insoluble in any solvent.
Siegel et al., J. Controlled Release (1988) 8(2):179-182, employs hydrophobic polyamine hydrogels that swell selectively at low pHs to administer drugs orally in a manner that avoids premature release of drug in the oral cavity but permits release in the stomach. Such hydrogels would not be useful for delivering drugs selectively to the colon.